CZ307255B6 - A new method of preparing elvitegravir - Google Patents

Abstract

The solution relates to a method of preparing elvitegravir of formula I which is obtained by reacting an intermediate of formula V with 3-chloro-2-fluorobenzyl zinc bromide to form an intermediate of formula VII which is converted to the elvitegravir of formula I by reaction with the agents suitable for deprotection. The substituent X is Cl, Br, I, and PG is a trimethylsilyl protecting group suitable for protecting carboxyl functions or alcohols.

Description

Technical field

The invention relates to an improved process for the production of elvitegravir I,

O, which is currently in a phase III clinical trial for the treatment of HIV infection. The drug was discovered by Japan Tobacco and licensed by Gilead Sciences, a clinical development company.

BACKGROUND OF THE INVENTION

In the basic patent of Japan Tobacco, Inc. (US 7 176 220; EP 1 564 210; WO 2004/046 115) two analogous synthetic processes starting from 2,4-difluorobenzoic acid 1 are described. According to the first process outlined in Scheme 1, this starting material is first converted to benzoyl acrylate in several stages. This is substituted with (S) - (+) valinol 6 to enamine 7, which is subsequently cyclized to quinolone 8, whose free hydroxyl group is protected by reaction with methyl chloroformate to carbonate 9a. This was next reacted with 3-chloro-2-fluorobenzyl isobromide 11 (prepared from 3-chloro-2-fluorobenzyl bromide 10 under Negishi coupling conditions) in the presence of an organopalladium catalyst to afford the protected benzylquinolone derivative 12a. This is next alkaline deprotected to intermediate 13, which in the final step is reacted with sodium methoxide to the end product elvitegravir (Scheme 1).

- 1 GB 307255 B6

(1)

N-iodosuccinimide

H ₂ SO ₄

SOCI ₂

.COOEt

I (3) (2)

Ethyl ethyl

Ph-phenyl

Scheme l

The second procedure described in the basic patent is the same as that outlined in Scheme 1, except for intermediate 8, the hydroxyl group of which is protected with tert-butyldimethylsilyl chloride. The thus obtained protected silyl ether 9b is further subjected to Negishi coupling with 3-chloro-2-fluorobenzyl zinc bromide 11 in the presence of bis (dibenzylideneaeeton) palladium (0) and tris (2-10 furyl) phosphine to protected intermediate 12b. involves alkaline deprotection to hydroxy acid 13, followed by treatment with sodium methoxide (Scheme 2).

-2GB 307255 B6

Scheme 2

Matrix Laboratories patent application WO 2011/004 389 discloses a synthesis analogous to that of the basic patent utilizing the protection of hydroxyl by a tetrahydropyranyl group (Scheme 3).

A more recent patent of Gilead Sciences US 7,825,252 (Scheme 4) is based on 2,4-dimethoxybenzoic acid 14. Thus, the reaction sequence is converted to the methyl ester 16, whose ester 17 is subsequently converted to the β-ketoester by reaction with 3-chloro-2-fluorobenzylzinc bromide 11. 20. Its reaction with dimethylformamide dimethylacetal affords benzoyl acrylate 21, which in turn provides the (S) - (+) - valinol 6 with enamine 22. Its hydroxyl group is protected in the next step by reaction with tert-butyldimethylsilyl chloride and the resulting 23 is subsequently cyclized to In the final step, both the ethyl ester is hydrolyzed and the TBDMS protecting group is removed (Scheme 4).

-4GB 307255 B6

Italy (23)

K ₂ CO ₃ n-Bu ₄ PBr toluene

Scheme 4

The process disclosed in Gilead Sciences US Patent No. 7,825,252 utilizes analogous quinolone ring syntheses to those already described, but with a different method of construction of key intermediates (Scheme 5). In the first step of this synthesis, the bromoacid 15 is first converted to the magnesium salt, followed by the addition of butyllithium to the substituted benzaldehyde 25 to the hydroxyacid 26. Subsequently, the hydroxy group is reduced to triethylsilane to acid 18. It is further converted to imidazole by reaction with carbonyldiimidazole. functional derivative 27, which subsequently reacts with potassium ethyl malonate to form the β-ketoester 20. The further procedure is already the same as above (Scheme 5).

F

(25)

THF, tetrahydrofuran

TFA ... trifluoroacetic acid

CDI ... carbonyldiimidazole

Scheme 5

SUMMARY OF THE INVENTION

An object of the present invention is an improved process for producing elvitegravir of formula I,

which is based on intermediate (II)

(II) obtainable from intermediate (III)

-6GB 307255 B6

(III), wherein X is Cl, Br, I and wherein R is (un) branched C 1 -C 4 alkyl, starting from the potentially very cheap 2,4-dimethoxyacetophenone (IV), produced in two steps from resorcinol, which is commercially commercial available and is produced in tonnes quantities.

(IV)

The main advantage of the process is the possibility of obtaining a highly pure intermediate (Ha, X = Br) which is not yet described in the literature and surprisingly converting it to elvitegravir, where after protecting both free functional groups coupling is carried out using 3-chloro-2fluorobenzylzinc bromide. a suitable catalyst, for example a palladium catalyst. As a rule, the purity of the intermediate IIa according to HPLC exceeds 99%.

Scheme 6

The group X may be chlorine, bromine or iodine, with the preferred compound being II, wherein X = Br (IIa). The general protecting group PG may be, for example, trimethylsilyl, or other protecting groups suitable for protecting an oxygen atom, such as di-Z-butyldimethylsilyl, benzyl, tetrahydropyranyl, tetrahydrofuranyl, others are listed, for example, in Protective Groups in Organic Synthesis, Third Edition. Theodora W. Greene, Peter G.M. Wuts, John Wiley, 1999. Substances V and VII need not be preferably isolated. Finally, elvitegravir is obtained by easy deprotection - the carboxyl protecting group is removed with water, alcohol, the hydroxyl protecting group is removed by reaction with dilute aqueous acid or water at a higher temperature.

Intermediate II was obtained following the procedure of Scheme 7.

Scheme 7

Preferably, the compounds VIII and IX need not be isolated.

Reactions were routinely monitored by HPLC on an HP 1050 equipped with a Phenomenex Luna 5μ Cl8 (2), 250 x 4.6 mm column equipped with a 227 nm UV detector. Phase A: 1.2 g NaH ₂ PO ₄ / l 1 water (pH = 3.0; Phase B: acetonitrile)

The invention is illustrated by the following examples. These examples, which illustrate the improvement of the process according to the invention, are purely illustrative and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(.S ') - Methyl 3- (1-hydroxy-3-methylbutan-2-ylamino) -2- (5-bromo-2,4-dimethoxybenzoyl) acrylate (IIIa, X = Br)

To a suspension of methyl 2- (5-bromo-2,4-dimethoxybenzoyl) -3- (dimethylamino) acrylate (Vlaa; 16.4 g, 44 mmol) in methanol (120 mL) was added a solution of ( _? S ') - ( +) - Linol (5 g, 48.5 mmol) in methanol (20 mL) and the mixture was stirred at room temperature for 1 h. The mixture was evaporated to 1/3 volume and after cooling the precipitated crystals were sucked off, washed with hexane (25 mL). ) and water (2 x 25 mL). After drying, 18.2 g (96%) of mp 141-145 ° C were obtained with HPLC purity of 98.5%. 1 H NMR (250 MHz, CDCl ₃ ) δ (ppm): 10.86 (bt, 1H), 7.95 (d, 1H), 7.52 (s, 1H), 6.41 (s, 1H) ,

-8GB 307255 B6

3.92 (s, 3H), 3.63-3.78 (m, 5H), 3.53 (s, 3H), 3.05-3.12 (m, 1H), 1.92-2, Δ O (m, 1H), 0.95-1.01 (m, 6H).

Example 2

6-Bromo-1- (1-hydroxy-3-methylbutan-2-yl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IIa)

To a suspension of IIIa (40 g, 93 mmol) in acetonitrile (80 mL) was added bistrimethylsilylacetamide (44 g, 216 mmol), and the suspension was stirred for 30 minutes at 25 ° C and for 3.5 hours at 70 ° C to 75 °. C. After addition of water (40 g), the reaction mixture was kept at 70 ° C for 2 hours and then allowed to stir at 25 ° C for 18 hours. Potassium hydroxide (8 g, 143 mmol) in water (50 mL) was added and the reaction mixture was allowed to stir for 3 h at 25 ° C. Acetic acid (12 g) was added and the resulting suspension was stirred at 50 ° C for 0.5 h, cooled to 25 ° C over 3 h, aspirated and washed to give a yellowish crystalline solid (34.4 g; 96). %, HPLC 99.6%). M.p. 255 DEG-257 DEG. 1 H NMR (250 MHz, DMSO) δ (ppm): 15.12 (s, 1H), 8.92 (s, 1H), 8.49 (s, 1H), 7.55 (s, 1H), 5 22 (t, 1H); 4.02 (m, 1H); 3.81 (s, 3H); 3.78 (m, 2H); 1.16 (d, 3H); 3H).

Example 3 (> S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxy-3-methylbutan-2-yl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid acid - elvitegravir (I)

To a suspension of 6-bromo-1- (1-hydroxy-3-methylbutan-2-yl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IIIa, 1.3 g, 3.38) mmol) in tetrahydrofuran (13 mL) was added bistrimethylsilylacetamide (1.95 g) and the mixture was stirred at 25 ° C for 10 min. PdCl ₂ (PPh ₃ ) 2 (39 mg) was added as a catalyst and 10 mL of a solution of 3-chloro-2-fluorobenzyl zinc bromide in tetrahydrofuran (0.5 M) was added over 1 h at 60 ° C, the mixture was further heated at 60 ° C for 1.5 h. Deň: 32 ° C. After cooling to 25 ° C, 10 ml of water, 0.5 g of 5% HCl was added to the solution, the mixture was further stirred for 30 minutes, saturated ammonium chloride was added and the product was extracted into ethyl acetate. Evaporation and crystallization from methanol gave 1.31 g (86%) of elvitegravir. Mp 161-163 ° C. 1 H NMR (250 MHz, CDCl ₃ ) δ (ppm): 15.68 (s, 1H), 8.76 (s, 1H), 8.14 (s, 1H), 7.21 (s, 1H) 6.95-7.04 (m, 3H), 4.47 (m, 1H), 4.14 (d, 2H), 3.99 (s, 3H), 2.39 (m, 1H), 1.19 (d, 3H); 0.78 (d, 3H);

1.1. 193-202 ° C (dec.) And HPLC purity 96.3%.

Claims (5)

PATENT CLAIMS A process for the preparation of elvitegravir of formula I, which is obtained by reacting an intermediate of formula V wherein X is Cl, Br, I and wherein PG is a trimethylsilyl protecting group with 3-chloro-2-fluorobenzylzinc bromide to form an intermediate of formula VII (VII) which is converted to elvitegravir of formula I by reaction with reagents suitable for deprotection. A process according to claim 1, characterized in that the intermediate of formula (V) is obtained from a compound of formula (II) by reaction with a preservative (II) wherein X is Cl, Br or iodine. A process according to claim 1, wherein the intermediate of formula V is obtained from compound 11a by reaction with a preservative (IIa). A compound of formula IIa, which is an intermediate in the production process of claim 1. (Ha). The process for producing elvitegravir according to claim 1, wherein the metastable intermediate of formula VII (VII) is converted to elvitegravir by treatment with dilute hydrochloric acid or other weak acid or water at a higher temperature.